This study reports cryo-EM structures of the full-length human A3AR bound to selective agonists CF101 and CF102 in complex with G protein at 3.3-3.2 Å resolution. The agonists occupy the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in A3AR ligand selectivity and receptor activation. Key mutations in a unique sub-pocket significantly impact receptor activation. Comparative analysis with the inactive A2AR structure highlights a conserved activation mechanism. The findings provide insights into molecular recognition and signaling of A3AR, aiding in the design of subtype-selective adenosine receptor ligands. A3AR is a promising therapeutic target for inflammatory and cancerous conditions. The structures reveal the mechanisms of ligand recognition and activation in A3AR, providing valuable insights for designing effective therapies for conditions like cancer and inflammation. The study also highlights the role of ECL3 in A3AR subtype selectivity and the importance of specific residues in ligand binding. The results demonstrate the structural basis of A3AR activation and G protein coupling, offering a deeper understanding of the molecular mechanisms governing ligand recognition, signaling, and subtype selectivity. The findings pave the way for structure-guided design of selective ligands targeting adenosine receptors for the treatment of cancer, inflammation, and other diseases.This study reports cryo-EM structures of the full-length human A3AR bound to selective agonists CF101 and CF102 in complex with G protein at 3.3-3.2 Å resolution. The agonists occupy the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in A3AR ligand selectivity and receptor activation. Key mutations in a unique sub-pocket significantly impact receptor activation. Comparative analysis with the inactive A2AR structure highlights a conserved activation mechanism. The findings provide insights into molecular recognition and signaling of A3AR, aiding in the design of subtype-selective adenosine receptor ligands. A3AR is a promising therapeutic target for inflammatory and cancerous conditions. The structures reveal the mechanisms of ligand recognition and activation in A3AR, providing valuable insights for designing effective therapies for conditions like cancer and inflammation. The study also highlights the role of ECL3 in A3AR subtype selectivity and the importance of specific residues in ligand binding. The results demonstrate the structural basis of A3AR activation and G protein coupling, offering a deeper understanding of the molecular mechanisms governing ligand recognition, signaling, and subtype selectivity. The findings pave the way for structure-guided design of selective ligands targeting adenosine receptors for the treatment of cancer, inflammation, and other diseases.